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Adenosine derivative formulations for medical imaging

a technology of adenosine derivatives and formulations, applied in the field of adenosine derivative formulations, can solve the problems of many patients absolutely not being able to exercise to any satisfactory level, many adenosine derivatives can be very difficult to solubilize in aqueous media, and many patients cannot achieve satisfactory exercise. the effect of reducing the number of patients

Inactive Publication Date: 2008-09-11
ADENOSINE THERAPEUTICS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The invention in a first embodiment is directed to a stable composition useful for myocardial perfusion imaging, comprising one or more 2-alkynyladenosine derivatives, and a solvent consisting essentially of water and hydroxypropyl-β-cyclodextrin (which may also be referred to herein as hydroxypropylether-β-cyclodextrin).

Problems solved by technology

Many patients absolutely cannot exercise to any satisfactory level, due to peripheral vascular disease, medications, poor patient motivation, and a variety of other coexisting conditions.
Therefore, exercise may not always be an option.
Unfortunately, many adenosine derivatives can be very difficult to solubilize in aqueous media.
There are also long-range stability issues associated with adenosine-based formulations.
However, stability issues may still persist with one or more of these compounds.

Method used

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  • Adenosine derivative formulations for medical imaging
  • Adenosine derivative formulations for medical imaging
  • Adenosine derivative formulations for medical imaging

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0043]The following composition was prepared as hereinabove described:

ComponentsAmount or DescriptionMethyl trans-4-[3-[6-amino-9-(N-ethyl-β-D-100 μg / mLribofuranosyluronamide)-9H-purin-2-yl]prop-2-ynyl]cyclohexane carboxylateSodium Citrate Buffer10 mM at pH 4.8 ± 0.2Hydroxypropyl-β-2% by weightCyclodextrin(CAS 128446-35-5)(Hydroxypropyl Betadex[USP])WFI (water for injection)Q.S.HeadspaceAirFill Volume3 mL

[0044]After preparation, the above formulation was aluminum crimp-sealed in a 5 cc tubing vial, and closed with a 20mm serum stopper. Also prepared was a formulation containing 50 μg / mL of active substance, together with 1% by weight of hydroxypropyl-β-cyclodextrin.

example 2

[0045]The present study established the bioequivalency of the pharmacokinetic parameters for one formulation according to a preferred embodiment of the invention versus another formulation in an anesthetized open chest canine model using the same adenosine analog. Five female mongrel dogs, 1.5-2 years of age (11-15 kg) were used. After surgical instrumentation and a stabilization period, each dog received a bolus intravenous injection of adenosine (300 μg / kg) as a reference control followed by four intravenous doses (noncumulative) of Formulation 1 (the invention) and Formulation 2 (a lyophilized formulation) (two 1 μg / kg doses of each formulation). Blood samples were collected at 0 (pre-dose), 1, 3, 5, 7, 10, 15 and 30 minutes post-injection of each dose for determination of plasma levels of the active drug substance adenosine analog and the carboxylic acid metabolite by LC / MS / MS. Pharmacokinetic (PK) analysis included Cmax, area under the time-plasma concentration curve (AUC), cle...

example 3

[0049]This example illustrates the comparative stability of adenosine derivative compositions using hydroxypropyl-β-cyclodextrin as part of the invention, versus those containing hydroxyethyl-β-cyclodextrin.

[0050]A solution of methyl trans4-[3-[6-amino-9-(N-ethyl-β-D-ribofuranosyluronamide)-9H-purin-2-yl]prop-2-ynyl]cyclohexane carboxylate at 50 μg / mL was prepared in 10 mM citrate buffer at pH 4.8 with 1% (w / v) of hydroxypropyl-62 -cyclodextrin. A similar solution was prepared except that the 1% (w / v) hydroxypropyl-β-cyclodextrin was replaced with 1% (w / v) hydroxyethyl-β-cyclodextrin. Both solutions were stored at 70° C. for a period of fourteen days. The stability of the adenosine derivative was evaluated over the fourteen day period using chromatography to measure the increase in the primary degradation product, which is generated by hydrolysis of the methyl ester to form the acid by the reaction shown below.

[0051]A plot of the amount of the acid (% w / w relative to the adenosine d...

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Abstract

A stable composition useful for myocardial perfusion imaging contains one or more 2-alkynyladenosine derivatives; and a solvent which is made up of water and hydroxypropyl-β-cyclodextrin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the priority benefits of U.S. Provisional Application No. 60 / 885,489, filed 18 Jan. 2007, which is expressly incorporated fully herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to novel formulations of adenosine derivatives which are storage stable and useful for medical imaging, in particular myocardial perfusion imaging.BACKGROUND OF THE INVENTION[0003]Adequate coronary vasodilation is essential to myocardial perfusion imaging. Coronary vasodilation increases coronary blood flow. This increase creates differences in the distribution of the imaging agent great enough to identify regions supplied by stenosed coronary vessels and to distinguish problem areas from healthy tissue.[0004]Exercise stress testing often is employed for dilating coronary vessels, hence increasing coronary blood flow. However, maximum exercise levels are often required for sufficient vasodilation, and exer...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00A61K31/7076
CPCA61K47/48969B82Y5/00A61K49/0002A61K47/6951A61P9/08
Inventor THAKUR, AJIT B.ZDANKIEWICZ, DIANNE D.HSU, HSUN-WENCASTNER, JAMES F.ANDERSON, JAMES E.
Owner ADENOSINE THERAPEUTICS
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